The drug industry has continuously depended upon the discovery of new compounds, which can be used to treat a continuously increasing number of diseases. As the ability to detect various pathogenic agents increases, one has the opportunity to develop new therapeutic agents which have specificity for one or more pathogens. In addition, there are numerous cellular markers (including receptors) associated with individual cells, as related to tissues, mobile cells, organs, levels of differentiation, and the like. In many instances, binding to these markers will transduce signals across the membrane, so as to initiate or inhibit intracellular processes. These processes may involve activation/inactivation, differentiation, secretion, proliferation, cytotoxic activity, metabolism of various nutrients, and the like. In many situations, one wishes to have compounds which act as agonists or antagonists to these various processes. In addition, one may wish to selectively kill various cells or deactivate various cells. For example, with cancers it would be very desirable to be able to selectively kill the cancer cells, while not affecting normal cells.
Furthermore, many of the drugs which are used today have a plurality of effects. Rather than exerting the particular effect of interest, the drugs bring with them a train of other effects, which may be deleterious to the host. In most cases, the deleterious effects are because the drug is not as specific for the target as one would wish, so as to bind other targets and induce the undesirable side effects.
The synthesizing of new compounds or identifying new compounds in nature is extraordinarily expensive. Therefore, for the most part, the repertoire of potential pharmacophores is relatively limited. Rational drug design has provided some insights, but has not been as successful as one hoped. The situation is particularly complicated because it has been found that as a drug binds to its' receptor, the conformation of the receptor may change. Therefore, the spatial conformation of the binding site may undergo substantial changes depending upon the manner in which the receptor and drug interact, and this has important implications when designing drugs.
In order to add greater variety to compounds available for drug development, combinatorial libraries have been created. These libraries are predicated on being able to prepare large numbers of compounds, particularly thousands of compounds, within a relatively short time; combinatorial libraries can be randomly created without a motif, where the diversity can be 10.sup.12 compounds. Initially, the compounds were for the most part oligomers, where the same bifunctionality was employed, having different side groups, by being added successively to form the oligomer. This approach lent itself very well to oligopeptides and oligonucleotides. Indeed, the oligopeptides have been expanded to using a wide variety of amino acid analogs, rather than the naturally occurring amino acids. In this way, chains having very different side groups and different intervening moieties between the carboxyl group and the amino group have been prepared. More recently, combinatorial libraries have been shown to be capable of incorporating synthetic organic molecules based on a central pharmacophore.
With combinatorial libraries, the diversity of compounds is no longer the limiting factor in drug development. Instead, screening for compound activity has become the limiting step. In order to be able to screen large numbers of compounds rapidly for a particular characteristic, one needs to have relatively inexpensive, rapid techniques, which have a high degree of fidelity. In addition, the technique should afford the ability to identify the compound which has the desired therapeutic characteristic. Thus, any assay technique should allow for procedures where activity can be readily detected and the identity of the compound having the activity identified.
Relevant Literature
See Galili et al., J. Exp. Med. (1985) 162:573-5;82; Galili et al, PNAS (1987) 84:1369-1373; and Galili et al., Blood (1993) 82:2485-2493. See also, references concerned with combinatorial libraries, supra. See McClellan, Oral 34250! of the Third International Congress for xenotransplantation abstracts, Sep. 27-Oct. 1, 1995 for a peptide mimeotope of Gal .alpha.-1,3-galactose.